Simulated Moving Bed Chromatography in the Pharmaceutical Industry Ron Bates Bristol-Myers Squibb April 19, 2004
Transcript
Slide 1
Simulated Moving Bed Chromatography in the Pharmaceutical
Industry Ron Bates Bristol-Myers Squibb April 19, 2004
Slide 2
Outline Short Biography What is Bristol-Myers Squibb
Chromatography Batch vs continuous HPLC, LC, SMB, P-CAC Simulated
Moving Bed Chromatography Introduction Theory (brief) Operation
Applications in the Pharmaceutical Industry
Slide 3
B.S. Chemical Engineering, RPI, 1993 Ph.D. Biochemical
Engineering, University of Maryland, Baltimore County, 1999 Focus:
ion-exchange chromatography Pfizer, Groton, CT, 1999-2003 Focus:
small molecule chromatography, HPLC, LC, SFC, SMB, FLASH,
extraction, crystallization, precipitation Bristol-Myers Squibb,
Syracuse, NY, 2003-present Focus: protein chromatography
Slide 4
Bristol-Myers Squibb Top-ten pharmaceutical company Products in
numerous therapeutic areas Cardiovascular & Metabolic
DiseasesMental Health Pravachol, CoumadinAbilify Headache and
MigraneInfectious Diseases ExcedrinReyataz, Sustiva Oncology
Erbitux, Taxol Strong pipeline focused in 10 therapeutic areas
Oncology, Cardiovascular, Infectious Diseases, Inflammation, etc.
Sites around the world U.S. Research/Manufacturing sites MA, NY,
NJ, CT, IL, Puerto Rico
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Bristol-Myers Squibb Syracuse, NY Clinical and Commercial
Manufacturing Plant Small-molecule pilot plants Process development
and optimization Clinical manufacturing Penicillin-based products
Last US-based Penicillin manufacturer Bio-synthetic products
Biotechnology Development, Manufacturing, Analytical Biosciences,
Quality Control / Assurance
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Bristol-Myers Squibb Syracuse, NY - Biotechnology Two lead
protein therapeutics Abatacept: commericial in 2005
Commercial-scale manufacturing Commercial launch out of Syracuse
Facility BLA filing Dec. 2004 LEA29Y: Phase III clinical trials in
2005 Development for next generation process Clinical production in
2004 Expansion in analytical and quality groups to support
processes
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Batch vs. Continuous Chromatography
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Discrete starting and ending points Example: 10 minute HPLC
cycle Types: GC, HPLC, FLASH, FPLC, LC, etc. Can be run in many
modes: Linear, overloaded, frontal, etc. Batch Chromatography
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(Raffinate) Feed Desorbent Effluent to Waste Load Elution
Effluent to Waste DesorbentElution (Extract) (To Waste) Strong
Solvent Regeneration Reference: Linda Wang, Perdue University
Slide 10
Batch Chromatography Empty zone
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Continuous Chromatography Feed is loaded onto column and
product is collected continuously Annular (P-CAC) Preparative
continuous annular chromatography Countercurrent Simulated moving
bed chromatography (SMB) Feed column
What is SMB SMB is Simulated Moving Bed Chromatography. SMB is
continuous countercurrent chromatography. The feed is pumped into
the system and two (or more) product streams are continuously
collected. SMB has been used for the production of millions of tons
of bulk commodities (p-xylene, high fructose corn syrup, etc...)
for the past four decades. Due to improvements in column and
equipment technology, SMB has recently been used in the
pharmaceutical industry (Sandoz, SmithKline, UCB, Pfizer). HPLC
costs: $100/kg to $5000/kg SMB costs: $50/kg to $200/kg
Slide 18
SMB versus HPLC Advantages of SMB: Lower solvent utilization
(up to 10 times less than batch HPLC) Generally can use less
expensive, larger stationary phases Able to get high recovery and
high purity Sometimes better productivity Lower labor and QC costs
Only partial separation of solutes is required to obtain high
purity. Higher yield than batch 10% more than batch. High
throughput 5 to 10 fold increase. Lower solvent consumption An
order of magnitude lower. Continuous process. Disadvantage of SMB:
Binary separation only Complexity
Slide 19
Commercial Applications of SMB Hydrocarbons Sugars
Agrochemicals Antibiotics Peptides Chiral Drugs Gaining tremendous
momentum FDA approves of the technology Chiral resin manufacturers
sell resins specifically made for SMB Proteins? Useful as polishing
step? SEC: remove aggregated form of product Multicomponent
separations more difficult than traditional uses 8, 12, even 16
zone systems being examined
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Basic Principle Mobile Phase Feed Continuous Countercurrent
Chromatography stationary column A sample is injected in the centre
of a stationary column The two components move at different speeds
and are separated If we now move the column from right to left, at
a speed halfway between that of the solutes, they now move in
different directions...
Slide 21
Basic Principle Mobile Phase Feed column The two solutes now
move in different directions relative to a stationary observer. If
the column is very long, the bands will continue to separate.
Continuous Countercurrent Chromatography
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Basic Principle Mobile Phase Feed column If we continue to add
sample at the center, the components will continue to separate
Continuous Countercurrent Chromatography
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This is clearly a continuous system, but there are problems.
The column needs to be of infinite length, the actual moving of
solids is very difficult and some way to introduce and remove the
sample and the products are needed. We solve this by cutting the
column into small segments and simulating the moving of them Basic
Principle Mobile Phase Feed column Continuous Countercurrent
Chromatography
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The feed and solvent inlets are now placed between the segments
and are moved each time a segment is moved from one end to the
other Basic Principle Mobile Phase Feed column Continuous
Countercurrent Chromatography
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Products are removed by bleeding off a carefully calculated
flow at suitable exit points. This changes the velocity of the
bands in the column and forces the products to move toward the
ports This ensures that the column segments are clean before they
are moved and that the solvent can be recycled directly back
through the system Mobile Phase Basic Principle Mobile Phase Feed
column Continuous Countercurrent Chromatography
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True Moving Bed
Slide 27
Binary Separation in a True Moving Bed Desorbent Raffinate
Extract Feed Extract Raffinate Time : t Time : t + t Reference:
Linda Wang, Perdue University
Slide 28
Binary Separation in a True Moving Bed Desorbent Raffinate
Extract Feed ExtractRaffinate Time : t + 3 t Feed Time : t + 2 t
Desorbent Reference: Linda Wang, Perdue University
Slide 29
Binary Separation in a True Moving Bed Desorbent Raffinate
Extract Feed Extract Raffinate Time : t + 4 t Time : t + 5 t
Reference: Linda Wang, Perdue University
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TMB to SMB Since its very difficult to move solids, true
countercurrent chromatography does not exist. Instead, the bed is
broken into many fractions and their movement is simulated by
changing the inlet and outlet ports
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Simplified SMB - 1 Feed Solvent ExtractRaffinate Feed Solvent
ExtractRaffinate The system is started..... A frontal elution
separation occurs in Section 3. 1234
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Simplified SMB - 2 Feed Solvent ExtractRaffinate Feed Solvent
ExtractRaffinate The separation continues..... Eventually the front
of pure product 1 reaches the outlet. It is distributed between the
final Section and the product port
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Feed Solvent ExtractRaffinate Simplified SMB - 3 Feed Solvent
ExtractRaffinate Finally, the mixed product reaches the outlet. To
avoid collecting impure material, it is necessary to move the
columns 1 position upstream.
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Feed Solvent ExtractRaffinate Simplified SMB - 4 Feed Solvent
ExtractRaffinate The frontal separation continues; at the same
time, the slow moving product starts to separate from the tail of
the mixed product band in Section 2 Eventually the fast moving
product again reaches the outlet and more pure product is
collected.
Slide 35
Feed Solvent Extract Raffinate Simplified SMB - 5 When the
mixed band reaches the end of Section 3 its tail has left Section 2
(if the separation has been correctly designed) and only pure
product 2 remains in Section 2. Feed Solvent Extract Raffinate To
avoid collecting impure raffinate, the columns are moved once more.
Now, the pure component 2 is in Section 1.
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Feed Solvent Extract Raffinate Simplified SMB - 6 Feed Solvent
Extract Raffinate The second component is now collected at the
Extract port while the separation continues in Sections 2 and 3.
The faster component reaches the Raffinate port and is again
collected; note that the outlet concentrations are neither constant
nor concurrent.
Slide 37
Feed Solvent Extract Raffinate Simplified SMB - 7 Feed Solvent
Extract Raffinate Eventually, the mixed zone reaches the raffinate
port and the columns are again switched. This simplified system is
now in a steady state mode and will continue to cycle. Switch
Slide 38
The moving of the bed is simulated by moving the points of feed
and mobile phase addition, as well as the points of raffinate and
extract removal while keeping the column positions fixed. Time = 0
Extract Feed Raffinate Mobile Phase Feed Raffinate Time = 1 Mobile
Phase Extract Packed Column
Slide 39
The zones are made up of one or more columns Six-column SMB
System Eight-column SMB system IIIIIIIV IIIIIIIV IIIIIIIVIIIIIIIV
SMB Configurations
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SMB Operation
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Slide 42
Theory Governing Equations For another day Maybe
Slide 43
Theory Working Equations / Definitions k 1 = capacity factor =
(t r -t 0 ) / t 0 = k 2 / k 1 R s = 2* (t r1 -t r2 ) / (w 1 -w 2
)
Slide 44
SMB Method Development 1.Start with linear batch experiments
2.Increase either mass or volume of load to overload the column
3.Calculate isotherm 4.Determine resistance to mass transfer (if
important) 5.Calculate necessary flow rates 6.Optimize (either
on-the-fly or with a proven model)
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Linear Chromatography
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Batch Chromatography Experiments Feed concentration As
concentrated as possible to minimize disruption to Zone III
velocity Need to run batch experiments at appropriate
concentrations and solvents Desorbent composition Solubility of
products Strength Trade-off between time and mobile phase
utilization Sorbent Capacity, selectivity, resolving power
Slide 47
Feed Concentration Feed concentration: Consider two systems A:
Concentrated feed B: Dilute feed Run batch experiments to examine
effect of concentration
Slide 48
Desorbent composition Multiple trade-offs: Solubility of
products and effectiveness of the solvent Not always complimentary
Often solubility dictates solvent composition Speed Low k = high
throughput More wear and tear on equipment Larger system needed
Large k = low throughput Less wear and tear Smaller system
acceptable
Slide 49
Choice of Sorbent Capacity: higher = better? Selectivity:
higher = better? Resolving power: higher R s = better?
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Linear Chromatography
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Volume Overloading
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Batch Chromatography to SMB Initial Operating Conditions
Determine optimal feed concentration, stationary phase and mobile
phase composition (highest with lowest capacity factors) Calculate
isotherm and mass transfer resistances Either use software package
or rules of thumb to generate initial SMB flow rates
Slide 53
Zone velocities v I = v Recycle + v D v II = v I - v X v III =
v II + v F v Recycle = v III - v Raff Solvent Mass Balances Flow
Rates IIIIIIIV vIvI v II v III v Recycle vXvX v Raff vFvF vDvD
Overall Mass Balance v D + v F = v X + v Raff
Slide 54
Flow rates Commercial SMB design models available Given batch
results from 5-10 column experiments Flow rate, feed
concentrations, retention times Solubility data Predict zone
velocities, productivities Problems: Usually assumes simple
adsorption model and lumped mass transfer coefficients Often
difficult to interpret overloaded chromatograms Rules of Thumb
Educated guesses based upon batch results from linear and
overloaded experiments V II and V III ratio (based upon retention
times) V I to flush back-side of slowest component from zone I Feed
concentration and flow rate based upon solubility data and solvent
mass balance
Slide 55
Period The period is the time a column stays in one zone also
called switching time. Changing the period has the effect of
changing all 4 zones simultaneously, thus either speeding up or
slowing down the solutes
Slide 56
Example of switching time
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SMB Optimization Independent variables: Flow rates Recycle,
Desorbent, Raffinate, Extract, Feed Period (switching time) Thats
it. Procedure: Get the system bound, manipulate the flow rates to
maximize throughput at required purity
Slide 58
SMB Optimization IIIIIIIV vIvI v II v III v Recycle vXvX v Raff
vFvF vDvD Questions: What is the effect of increasing the Zone I
flow rate? How would one accomplish this? Zone II? Zone III? What
if the system is underutilized (i.e., more feed can be added to the
system) how would one do this without affecting the other zone flow
rates?
Slide 59
Two component SMB System Feed Desorbent Extract Raffinate Conc.
I II III IV Bed Position
Slide 60
SMB Optimization IIIIIIIV vIvI v II v III v Recycle vXvX v Raff
vFvF vDvD Questions: Extract contains too much of the weakly
adsorbed species what do you do? If situation was reversed?
Slide 61
Two component SMB System Feed Desorbent Extract Raffinate Conc.
I II III IV Bed Position
Slide 62
SMB Optimization IIIIIIIV vIvI v II v III v Recycle vXvX v Raff
vFvF vDvD Questions: Extract contains too much of the weakly
adsorbed species what do you do? If situation was reversed?
Slide 63
Two component SMB System Feed Desorbent Extract Raffinate Conc.
I II III IV Bed Position
Slide 64
Examples of SMB
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Two component SMB System
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Multi-component System Single-component pulse data Reference:
Linda Wang, Perdue University
Slide 67
Multi-Component SMB System Desorbent Extract (2, 3) Feed (1, 2,
3) Raffinate (1) I II IIIIV 1 Fast Solute 2 Intermediate Solute 3
Slow Solute Concentration Bed Position Reference: Linda Wang,
Perdue University
Slide 68
Complete Separation in Tandem SMB Column Number 05101520 0 0.5
1 C i /C F,i Des.Ext.FeedRaf. Sulfuric Acid Glucose Acetic Acid
05101520 0 0.5 1 C i /C F,i Des.Ext.FeedRaf. Reference: Linda Wang,
Perdue University
Slide 69
Profiles of a Parallel SMB Glucose yield: 94% Glucose purity:
99% Reference: Linda Wang, Perdue University